tbuckley/cabot-search huggingface dataset:
Transdiagnostic Connectome-Based Prediction of Craving
Authors: Kathleen A. Garrison, Rajita Sinha, Marc N. Potenza, Siyuan Gao, Qinghao Liang, Cheryl Lacadie, Dustin Scheinost
Journal: American Journal of Psychiatry (2023)

Objective: Craving is a central construct in the study of motivation and human behavior and is also a clinical symptom of substance and non-substance-related addictive disorders. Thus, craving represents a target for transdiagnostic modeling. Methods: The authors applied connectome-based predictive modeling (CPM) to functional connectivity data in a large (N=274) transdiagnostic sample of individuals with and without substance use–related conditions, to predict self-reported craving. Functional connectomes derived from three guided imagery conditions of personalized appetitive, stress, and neutral-relaxing experiences were used to predict craving rated before and after each imagery condition. The generalizability of the “craving network” was tested in an independent sample using functional connectomes derived from a cue-induced craving task collected before and after fasting to predict craving rated during fasting. Results: CPM successfully predicted craving, thereby identifying a transdiagnostic “craving network.” Anatomical localization of model contribution suggested that the strongest predictors of craving were regions of the salience, subcortical, and default mode networks. As external validation, in an independent sample, the “craving network” predicted food craving during fasting using data from a cue-induced craving task. Conclusions: These data provide a transdiagnostic perspective to a key phenomenological feature of addictive disorders—craving—and identify a common “craving network” across individuals with and without substance use–related disorders, thereby suggesting a neural signature for craving or urge for motivated behaviors.
Beta-blockade improves right ventricular diastolic function in exercising pulmonary arterial hypertension
Authors: Chinthaka B. Samaranayake, Aleksander Kempny, Robert Naeije, Michael Gatzoulis, Laura C. Price, Konstantinos Dimopoulos, Lan Zhao, Stephen J. Wort, Colm McCabe
Journal: European Respiratory Journal (2023)

Right ventricular (RV) function is a main determinant of outcome in pulmonary arterial hypertension (PAH) [1]. Increased neuro-humoral activation associated with decreased survival in PAH may worsen RV adaptation to increased afterload [2, 3]. There is rationale therefore for the use of β-blockers in PAH especially given their beneficial effect on RV function in experimental PAH models [4, 5]. Small clinical studies in PAH using bisoprolol and carvedilol have demonstrated acceptable patient tolerance, however no change in exercise capacity was seen and concerningly, resting cardiac output (CO) decreased despite unchanged or even mild improvement in RV ejection fraction (EF) [6, 7]. Moreover, in exercising PAH, associated with impaired RV adaptation to high afterload, acute effects of β-blockers on the RV are unstudied. In the present study, we reasoned that the acute administration of β-blockers in PAH patients might improve RV diastolic filling as has been observed in experimental PAH [5] and accordingly contribute to preservation of coupling of RV function to the pulmonary circulation during exercise. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of Interest: Pierre-Régis Burgel reports support for the present work from Vaincre la Mucoviscidose. Pierre-Régis Burgel reports grants from Boehringer Ingelheim, GSK, Vertex; consulting fees and lecture honoraria from Boehringer Ingelheim, GSK, AstraZeneca, Vertex, Chiesi, Pfizer, Novartis, Zambon, Insmed; outside the submitted work. Conflict of Interest: All authors have nothing to disclose.
Preterm birth and asthma and COPD in adulthood: a nationwide register study from two Nordic countries
Authors: Anna Pulakka, Kari Risnes, Johanna Metsälä, Suvi Alenius, Katriina Heikkilä, Sara Marie Nilsen, Pieta Näsänen-Gilmore, Peija Haaramo, Mika Gissler, Signe Opdahl, Eero Kajantie
Journal: European Respiratory Journal (2023)

Preterm birth affects lungs in several ways but few studies have follow-up until adulthood. We investigated the association of the entire spectrum of gestational ages with specialist care episodes for obstructive airway disease (asthma and chronic obstructive pulmonary disease (COPD)) at age 18-50 years.
Genome‐wide association study of tuberculosis in the western Chinese Han and Tibetan population
Authors: Hao Bai, Mengyuan Song, Shikun Lei, Lin Jiao, Xuejiao Hu, Tao Wu, Jiajia Song, Tangyuheng Liu, Wu Peng, Zhenzhen Zhao, Zirui Meng, Binwu Ying
Journal: MedComm (2023)

Abstract Tuberculosis (TB) remains a serious global public health threat. Accumulated evidence has demonstrated that human susceptibility to TB has a strong genetic basis. And different susceptibility single nucleotide polymorphisms (SNP) have been reported in different studies. To gain greater insight into the host susceptibility to TB, we perform a two‐stage genome‐wide association study to identify the susceptible loci of TB. In the discovery stage, 3116 (1532 TB patients and 1584 healthy controls) and 439 (211 TB patients and 228 healthy controls) individuals were genome‐wide genotyped from a western Chinese Han and Tibetan population, respectively. Based on the additive genetic model, we discovered 14 and three independent loci that had potential associations with TB susceptibility in the Chinese Han and Tibetan populations, respectively ( p &lt; 1 × 10 −5 ). Furthermore, we conducted an imputation‐based meta‐analysis on another two East Asia cohorts to replicate our findings. We identified one independent locus harbored by the human leukocyte antigen ( HLA ) class II genes that was genome‐wide significantly associated with TB (lead SNP rs111875628 with a p‐ value of 2.20 × 10 −9 ). Our findings suggest a novel mechanism of the interaction with the HLA class II genes and reinforce the importance of the HLA class II alleles in response to TB.
Xenogeneic cross-circulation for physiological support and recovery of ex vivo human livers
Authors: Wei Kelly Wu, Rei Ukita, Yatrik J. Patel, Michael Cortelli, Vincent Q. Trinh, Ioannis A. Ziogas, Sean A. Francois, Meredith Mentz, Nancy L. Cardwell, Jennifer R. Talackine, William M. Grogan, John W. Stokes, Youngmin A. Lee, Jinho Kim, Sophoclis P. Alexopoulos, Matthew Bacchetta
Journal: Hepatology (2023)

Background and Aims: The scarcity of suitable donor livers highlights a continuing need for innovation to recover organs with reversible injuries in liver transplantation. Approach and Results: Explanted human donor livers (n = 5) declined for transplantation were supported using xenogeneic cross-circulation of whole blood between livers and xeno-support swine. Livers and swine were assessed over 24 hours of xeno-support. Livers maintained normal global appearance, uniform perfusion, and preservation of histologic and subcellular architecture. Oxygen consumption increased by 75% ( p = 0.16). Lactate clearance increased from −0.4 ± 15.5% to 31.4 ± 19.0% ( p = 0.02). Blinded histopathologic assessment demonstrated improved injury scores at 24 hours compared with 12 hours. Vascular integrity and vasoconstrictive function were preserved. Bile volume and cholangiocellular viability markers improved for all livers. Biliary structural integrity was maintained. Conclusions: Xenogeneic cross-circulation provided multisystem physiological regulation of ex vivo human livers that enabled functional rehabilitation, histopathologic recovery, and improvement of viability markers. We envision xenogeneic cross-circulation as a complementary technique to other organ-preservation technologies in the recovery of marginal donor livers or as a research tool in the development of advanced bioengineering and pharmacologic strategies for organ recovery and rehabilitation.
The shaky foundations of simulating single-cell RNA sequencing data
Authors: Helena L. Crowell, Sarah X. Morillo Leonardo, Charlotte Soneson, Mark D. Robinson
Journal: Genome biology (2023)

Abstract Background With the emergence of hundreds of single-cell RNA-sequencing (scRNA-seq) datasets, the number of computational tools to analyze aspects of the generated data has grown rapidly. As a result, there is a recurring need to demonstrate whether newly developed methods are truly performant—on their own as well as in comparison to existing tools. Benchmark studies aim to consolidate the space of available methods for a given task and often use simulated data that provide a ground truth for evaluations, thus demanding a high quality standard results credible and transferable to real data. Results Here, we evaluated methods for synthetic scRNA-seq data generation in their ability to mimic experimental data. Besides comparing gene- and cell-level quality control summaries in both one- and two-dimensional settings, we further quantified these at the batch- and cluster-level. Secondly, we investigate the effect of simulators on clustering and batch correction method comparisons, and, thirdly, which and to what extent quality control summaries can capture reference-simulation similarity. Conclusions Our results suggest that most simulators are unable to accommodate complex designs without introducing artificial effects, they yield over-optimistic performance of integration and potentially unreliable ranking of clustering methods, and it is generally unknown which summaries are important to ensure effective simulation-based method comparisons.
Circulating and urinary tumour DNA in urothelial carcinoma — upper tract, lower tract and metastatic disease
Authors: Kyle M. Rose, Heather L. Huelster, Joshua J. Meeks, Bishoy M. Faltas, Guru P. Sonpavde, Seth P. Lerner, Jeffrey S. Ross, Philippe E. Spiess, G. Daniel Grass, Rohit K. Jain, Ashish M. Kamat, Aram Vosoughi, Liang Wang, Xuefeng Wang, Roger Li
Journal: Nature Reviews Urology (2023)
Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages
Authors: Michael A. Gonzalez, Daniel R. Lu, Maryam Yousefi, Ashley Kroll, Chen Hao Lo, Carlos G. Briseño, J. E. Vivienne Watson, Sergey Novitskiy, Vanessa Arias, Hong Zhou, Andres Plata Stapper, Min K. Tsai, Emily L. Ashkin, Christopher W. Murray, Chi-Ming Li, Monte M. Winslow, Kristin V. Tarbell
Journal: The Journal of Experimental Medicine (2023)

Phagocytosis is a key macrophage function, but how phagocytosis shapes tumor-associated macrophage (TAM) phenotypes and heterogeneity in solid tumors remains unclear. Here, we utilized both syngeneic and novel autochthonous lung tumor models in which neoplastic cells express the fluorophore tdTomato (tdTom) to identify TAMs that have phagocytosed neoplastic cells in vivo. Phagocytic tdTompos TAMs upregulated antigen presentation and anti-inflammatory proteins, but downregulated classic proinflammatory effectors compared to tdTomneg TAMs. Single-cell transcriptomic profiling identified TAM subset-specific and common gene expression changes associated with phagocytosis. We uncover a phagocytic signature that is predominated by oxidative phosphorylation (OXPHOS), ribosomal, and metabolic genes, and this signature correlates with worse clinical outcome in human lung cancer. Expression of OXPHOS proteins, mitochondrial content, and functional utilization of OXPHOS were increased in tdTompos TAMs. tdTompos tumor dendritic cells also display similar metabolic changes. Our identification of phagocytic TAMs as a distinct myeloid cell state links phagocytosis of neoplastic cells in vivo with OXPHOS and tumor-promoting phenotypes.
The Problem of Preventive Medicine
Journal: JAMA (2023)

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Evolving regulatory perspectives on digital health technologies for medicinal product development
Authors: Seya Colloud, Thomas Metcalfe, Scott Askin, Shibeshih Belachew, Johannes Ammann, Ernst Bos, Timothy Kilchenmann, Paul Strijbos, Damien Eggenspieler, Laurent Servais, Chloé Garay, Athanasios Konstantakopoulos, Armin Ritzhaupt, Thorsten Vetter, Claudia Vincenzi, Francesca Cerreta
Journal: npj Digital Medicine (2023)

Abstract Digital health technology tools (DHTTs) present real opportunities for accelerating innovation, improving patient care, reducing clinical trial duration and minimising risk in medicines development. This review is comprised of four case studies of DHTTs used throughout the lifecycle of medicinal products, starting from their development. These cases illustrate how the regulatory requirements of DHTTs used in medicines development are based on two European regulatory frameworks (medical device and the medicinal product regulations) and highlight the need for increased collaboration between various stakeholders, including regulators (medicines regulators and device bodies), pharmaceutical sponsors, manufacturers of devices and software, and academia. As illustrated in the examples, the complexity of the interactions is further increased by unique challenges related to DHTTs. These case studies are the main examples of DHTTs with a regulatory assessment thus far, providing an insight into the applicable current regulatory approach; they were selected by a group of authors, including regulatory specialists from pharmaceutical sponsors, technology experts, academic researchers and employees of the European Medicines Agency. For each case study, the challenges faced by sponsors and proposed potential solutions are discussed, and the benefit of a structured interaction among the different stakeholders is also highlighted.
Arterial Gerrymandering — Converting Veins to Arteries to Save Ischemic Limbs
Authors: Douglas E. Drachman
Journal: New England Journal of Medicine (2023)

Peripheral artery disease affects more than 200 million persons worldwide and is associated with substantial morbidity and mortality.1 More than 1 million persons in the United States have chronic limb-threatening ischemia, the most severe manifestation of peripheral artery disease, with a substantial risk of amputation and death 1 year after onset that exceeds 20%.2 Key treatments for chronic limb-threatening ischemia include guideline-directed medical therapy to address risk factors for systemic cardiovascular disease and revascularization of the affected leg to restore straight-line arterial flow to the foot and facilitate wound healing.3-5 Two major revascularization approaches can be pursued in patients with . . .
Conditionally activated affibody-based prodrug targeting EGFR demonstrates improved tumour selectivity
Authors: Charles Dahlsson Leitao, Anna Mestre Borras, Tianqi Xu, Maryam Oroujeni, Yongsheng Liu, Cornelia Westerberg, Jacob Clinton, Vladimir Tolmachev, Anna Orlova, Stefan Ståhl, Anzhelika Vorobyeva, John Löfblom
Journal: Journal of Controlled Release (2023)

Safety and efficacy of cancer-targeting treatments can be improved by conditional activation enabled by the distinct milieu of the tumour microenvironment. Proteases are intricately involved in tumourigenesis and commonly dysregulated with elevated expression and activity. Design of prodrug molecules with protease-dependent activation has the potential to increase tumour-selective targeting while decreasing exposure to healthy tissues, thus improving the safety profile for patients. Higher selectivity could also allow for administration of higher doses or use of more aggressive treatment options, leading to higher therapeutic efficacy. We have previously developed an affibody-based prodrug with conditional targeting of EGFR conferred by an anti-idiotypic affibody masking domain (ZB05). We could show that binding to endogenous EGFR on cancer cells in vitro was restored following proteolytic removal of ZB05. In this study we evaluate a novel affibody-based prodrug design, which incorporates a protease substrate sequence recognized by cancer-associated proteases and demonstrate the potential of this approach for selective tumour-targeting and shielded uptake in healthy tissues in vivo using tumour-bearing mice. This may widen the therapeutic index of cytotoxic EGFR-targeted therapeutics by decreasing side effects, improving selectivity of drug delivery, and enabling the use of more potent cytotoxic drugs.
Human habit neural circuitry may be perturbed in eating disorders
Authors: Allan R. Wang, Fiene Marie Kuijper, Daniel A. N. Barbosa, Kelsey E. Hagan, Eric Lee, Elizabeth Tong, Eun Young Choi, Jennifer A. McNab, Cara Bohon, Casey H. Halpern
Journal: Science Translational Medicine (2023)

Circuit-based mechanisms mediating the development and execution of habitual behaviors involve complex cortical-striatal interactions that have been investigated in animal models and more recently in humans. However, how human brain circuits implicated in habit formation may be perturbed in psychiatric disorders remains unclear. First, we identified the locations of the sensorimotor putamen and associative caudate in the human brain using probabilistic tractography from Human Connectome Project data. We found that multivariate connectivity of the sensorimotor putamen was altered in humans with binge eating disorder and bulimia nervosa and that the degree of alteration correlated with severity of disordered eating behavior. Furthermore, the extent of this circuit aberration correlated with mean diffusivity in the sensorimotor putamen and decreased basal dopamine D 2/3 receptor binding potential in the striatum, consistent with previously reported microstructural changes and dopamine signaling mediating habit learning in animal models. Our findings suggest a neural circuit that links habit learning and binge eating behavior in humans, which could, in part, explain the treatment-resistant behavior common to eating disorders and other psychiatric conditions.
Assessing the Burden of Suicide Death Associated With Nonoptimum Temperature in a Changing Climate
Authors: Yuchang Zhou, Ya Gao, Peng Yin, Cheng He, Wei Liu, Haidong Kan, Maigeng Zhou, Renjie Chen
Journal: JAMA Psychiatry (2023)

Importance Few studies have projected future suicide burden associated with daily temperatures in a warming climate. Objectives To assess the burden of suicide death associated with daily nonoptimal temperature and to project the change of suicide burden associated with nonoptimal temperature in different regions and seasons under various climate change scenarios. Design, Setting, and Participants Between January 1, 2013, and December 31, 2019, we conducted a time-stratified, case-control study among more than 430 000 individual suicide decedents from all counties in mainland China. Exposures Daily meteorological data were obtained from the European Centre for Medium-Range Weather Forecasts Reanalysis Fifth Generation (ERA5) reanalysis product. Historical and future temperature series were projected under 3 scenarios of greenhouse-gas emissions from 1980 to 2099, with 10 general circulation models. Main Outcomes and Measures The relative risk (RR) and burden of suicide death associated with nonoptimal temperature (ie, temperatures greater than or less than minimum-mortality temperature); the change of suicide burden associated with future climate warming in different regions and seasons under various climate change scenarios. Results Of 432 008 individuals (mean [SD] age; 57.6 [19.0] years; 253 093 male [58.6%]) who died by suicide, 85.8% (370 577) had a middle school education or less. The temperature-suicide associations were approximately linear, with increasing death risks at higher temperatures. The excess risk was more prominent among older adults (ie, ≥75 years; RR, 1.71; 95% CI, 1.46-1.99) and those with low education level (ie, middle school education or less; RR, 1.46; 95% CI, 1.36-1.57). There were 15.2% suicide deaths (95% estimated CI [eCI], 14.6%-15.6%) associated with nonoptimal temperature nationally. Consistent and drastic increases in excess suicide deaths over this century were predicted under the high-emission scenario, whereas a leveling-off trend after the mid–21st century was predicted under the medium- and low-emission scenarios. Nationally, compared with the historical period (1980-2009), excess suicide deaths were predicted to increase by 8.3% to 11.4% in the 2050s and 8.5% to 21.7% in the 2090s under the 3 scenarios. The projected percentage increments of excess suicide deaths were predicted to be greater in the South (55.0%; 95% eCI, 30.5%-85.6%) and in winter (54.5%; 95% eCI, 30.4%-77.0%) in the 2090s under the high-emission scenario. Conclusions and Relevance Findings of this nationwide case-control study suggest that higher temperature may be associated with the risk and burden of suicide death in China. These findings highlight the importance of implementing effective climate policies to reduce greenhouse gas emissions and tailoring public health policies to adapt to global warming.